Gamma-glutamyl hydrolase (GGH)

Gamma-glutamyl hydrolase is a lysosomal or secreted, thiol-dependent enzyme that hydrolyzes the γ-glutamyl bonds of folylpoly-γ-glutamates and antifolylpoly-γ-glutamates, converting them to monoglutamates by successive removal of γ-linked glutamate residues[2][3][4]. Encoded by the GGH gene, this enzyme regulates intracellular folate levels and plays a critical role in the activation and inactivation of antifolate chemotherapeutic agents such as methotrexate and pemetrexed, affecting their retention and efficacy inside cells[3]. GGH thus represents an important molecular target in oncology, particularly relevant for mechanisms of drug resistance; elevated GGH expression and activity can decrease therapeutic retention of antifolates and is being explored as a potential biomarker for drug response[3]. As an enzyme, it belongs to the peptidase family and demonstrates a characteristic mechanism involving catalysis at acidic pH, utilizing key catalytic residues such as Cys110 and His220 to mediate hydrolysis of polyglutamyl chains[1][3].

Other names

ConjugaseFolate conjugaseFolic acid conjugaseGamma-Glu-X carboxypeptidaseLysosomal gamma-glutamyl carboxypeptidasePteroyl-poly-gamma-glutamate hydrolaseCarboxypeptidase GPoly(gamma-glutamic acid) endohydrolasePolyglutamate hydrolasePoly(glutamic acid) hydrolase IIPteroylpoly-gamma-glutamyl hydrolase

Cleavage of polyglutamyl chains from antifolates, decreasing cellular retention and bioactivity of these drugs; Hydrolysis of polyglutamylated folates/antifolates, modulating drug and folate efficacy